PROJECT SUMMARY/ABSTRACT We propose to study the relation between prenatal and early postnatal exposure to metals?as well as metal exposures in adulthood?and cognitive function in older age, and the extent to which early life metal exposures modify the effects of adult exposures. We will also explore whether those exposures and cognitive outcomes are associated with changes in blood-derived extracellular vesicle (EV) micro RNA expression (miRNA), which could represent epigenetic mechanisms underlying associations. We will conduct a cohort study among a subset of participants in the original St. Louis Baby Tooth (SLBT) study who donated their baby teeth in the 1950s and 1960s. Based on our pilot work, we anticipate easily being able to enroll 1,000 former SLBT participants (500 men and 500 women) from whom we will collect blood and toenail samples, and all of whom will have responded to questionnaires and undergone cognitive testing. Prenatal and early postnatal exposure of the 1,000 to several metals will be assessed by measuring metals in baby tooth enamel (using laser-ablation inductively coupled plasma mass spectrometry). Adult metal exposures will be assessed by analyzing a series of toenail clippings collected roughly once a year. EVs will be isolated from the blood samples and analyzed for EV miRNA expression levels. The SLBT provides a unique setting that will allow us to have individual-level biomarkers of early life metal exposures in older adults on whom we can conduct cognitive function testing. This study setting allows us to have an unprecedented ability to examine whether early life exposures are related to late life cognitive health?a hypothesis suggested from animal research, but extremely hard to test in humans without the biomarker of such early exposure that the already collected baby teeth in the SLBT can provide.